chr13-32357886-ATA-TT

Position:

• chr13-32357886-ATA-TT

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7762_7764delATAinsTT​(p.Ile2588fs) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 7.45

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_000059.4 (BRCA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32357886-ATA-TT is Pathogenic according to our data. Variant chr13-32357886-ATA-TT is described in ClinVar as [Pathogenic]. Clinvar id is 233493.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7762_7764delATAinsTT	p.Ile2588fs	frameshift_variant, missense_variant	16/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7762_7764delATAinsTT	p.Ile2588fs	frameshift_variant, missense_variant	16/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7393_7395delATAinsTT	p.Ile2465fs	frameshift_variant, missense_variant	16/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7762_7764delATAinsTT		non_coding_transcript_exon_variant	15/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2018	Variant summary: BRCA2 c.7762_7764delinsTT (p.Ile2588PhefsX60) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Trp2626X, p.Met2634fsX14, and p.Arg2645fsX3). The variant was absent in 246218 control chromosomes (gnomAD). The variant, c.7762_7764delinsTT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Evans_2003, Lai_2015, Watson_2014, Borg_2010, Spearman_2008, Palma_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change creates a premature translational stop signal (p.Ile2588Phefs*60) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian or pancreatic cancer (PMID: 12960223, 15131399, 20104584, 30274973). This variant is also known as 7990delATAinsTT and 7990del3ins2. ClinVar contains an entry for this variant (Variation ID: 233493). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	The p.Ile2588fs (c.7762_7764delinsTT) variant in BRCA2 has been reported in at l east 8 individuals with BRCA2-associated cancers (Evans 2003, Lai 2015, Breast C ancer Information Core database, www.research.nhgri.nih.gov/bic/). While this va riant was absent from large population studies, the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a fr ameshift, which alters the protein?s amino acid sequence beginning at position 2 588 and leads to a premature termination codon 60 amino acids downstream. This a lteration is then predicted to lead to a truncated or absent protein. Heterozygo us loss of function of the BRCA2 gene is an established disease mechanism in her editary breast and ovarian cancer (HBOC). Additionally, the p.Ile2588fs variant has been classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIG MA Expert Panel (ClinVar SCV000282449.1). In summary, this variant meets our cri teria to be classified as pathogenic for HBOC in an autosomal dominant manner ba sed upon the predicted impact to the protein and presence in multiple affected i ndividuals. -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This variant deletes 3 nucleotides and inserts 2 nucleotides in exon 16 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 7990delATAinsTT or 7990del3ins2 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 5 individuals affected with pancreatic, breast, or ovarian cancer (PMID: 18824701, 20104584, 24307375, 30274973). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7990del3ins2 or 7990delATAinsTT; This variant is associated with the following publications: (PMID: 25685387, 27181684, 12960223, 20104584, 24307375, 23242139, 22706548, 18703817, 15131399, 26295337, 30274973, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2024	PP4_very_strong, PM5_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 25, 2024	The BRCA2 c.7762_7764delinsTT (p.Ile2588Phefs*60) variant (also known as 7762_7764delATAinsTT, 7990del3ins2, and 7990delATAinsTT) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals and families with an increased risk of or with a diagnosis of hereditary breast and/or ovarian cancer (PMIDs: 12960223 (2003), 15131399 (2004), 18703817 (2008), 20104584 (2010), 29446198 (2018), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/)) and pancreatic cancer (PMID: 22706548 (2012), 30274973 (2018)).This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	This variant deletes 3 nucleotides and inserts 2 nucleotides in exon 16 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 7990delATAinsTT or 7990del3ins2 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 5 individuals affected with pancreatic, breast, or ovarian cancer (PMID: 18824701, 20104584, 24307375, 30274973). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 12, 2015	The c.7762_7764delinsTT(also known as 7990delATAinsTT)pathogenic mutation, located in coding exon 15 of the BRCA2 gene, results from the deletion of threenucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon. This alteration has been previously identified in one family with HBOC(Evans DG, J. Med. Genet. 2003 Sep; 40(9):e107.). In addition to the clinical history presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).<br /> -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The BRCA2 p.Ile2588Phefs*60 variant was identified in 2 of 5068 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer (Borg 2010, Evans 2003). The variant was also identified in ClinVar (classified as pathogenic by ENIGMA expert panel, Invitae, GeneDx, Ambry Genetics and six other submitters). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.7762_7764delinsTT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2588 and leads to a premature stop codon at position 2647. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer (HBOC) and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 05, 2022

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs483353072; hg19: chr13-32932023;